Antibiotics are of immense value for combating infectious diseases. In recent decades, the effectiveness of antibiotics has been threatened by an inexorable rise in the prevalence of microbial drug resistance. Some important pathogens have serious resistance problems. Staphylococcus aureus is perhaps the most significant of these pathogens. It causes community and hospital acquired infections and is associated with high morbidity and mortality rates. Vancomycin has been used as the antibiotic of last resort to treat methicillin-resistance staphylococcus aureus infections (MRSA) with multiple resistance. Strains with some level of resistance to vancomycin (Vancomycin-intermediates-resistant S. aureus, VISA) have been known since 1996, but the newly identified highly resistant strain (VRSA) heralds a new stage in the battle with this pathogen. Other serious treatment problems include multidrug resistance in tuberculosis, vancomycin resistant enterococci (VRE), resistance owing to extended spectrum β-lactamases (ESBLs) in Enterobacteriaceae and Pseudomonas aeruginosa, and penicillin resistance in Streptococcus pneumoniae. 
A nation wide epidemic of multi drug resistant Salmonella typhi occurred in 1990 and has not yet fully subsided. Antimicrobial resistance among respiratory pathogens has become a common clinical problem, currently over 90% of Morexella catarrhalis and 25% of Haemophilus influenzae produce β lactamases, requiring treatment with a β lactamase stable cephalosporin or combination drugs. In the last several years, there has been a rapid increase in the number of strains resistant to penicillin, cephalosporins, macrolides and fluoroquinolones.
These circumstances have prompted efforts to develop new antibiotics that overcome the emerging antibiotic resistance bacteria. The amino acyl tRNA synthetases are essential enzymes found in all living organisms. These enzymes have emerged as an attractive target for the development of new antibiotics. Amino acyl tRNA synthetases charge tRNA molecules with their corresponding amino acid, an essential step in protein synthesis. There are 20 tRNA synthetases, most of which correspond to attractive broad-spectrum antibacterial targets. This is a validated target class in that pseudomonic acid A, also known as mupirocin, a natural product from Pseudominas fluorescens, inhibits isoleucyl tRNA synthase and is marketed as a topical antibiotic Bactropan. Other known natural products directed against amino acyl tRNA synthetases include borrelidin, furanomycin, granaticin, indolmycin, ochartoxin A, and cispentacin, none of them has been developed as antibiotic compounds.
U.S. Patent Application Nos. 2004/0224981 and 2003/0013724 disclose tRNA synthetase inhibitors. WO 00/18772 discloses condensed imidazolidinone as tRNA synthetase inhibitors. U.S. Pat. Nos. 5,191,093 and 4,916,155 disclose crystalline pseudomonate, processes for its production and its use in human and veterinary medicines. U.S. Pat. No. 4,916,155 discloses crystalline calcium pseudomonate or the hydrate thereof, and their use in human and veterinary medicine.
Novel synthetic compounds, which target tRNA synthetases, offer clear advantages as useful therapeutic agents to curb the threat of drug resistance.